Globin Peptide MG Pharma Incorporation
MG Pharma (English) > Globin Peptide (English)
Master The Health, From Saito to World
In 1989, MG Pharma found that Globin Peptide (Globin Digest) had the strongest effect to decrease neutral fat (triglyceride) among several food protein digests. One of the active component of Globin Peptide was proved to be tetra peptide, Val-Val-Tyr-Pro (VVYP).
Other physiological functions of Globin Peptide are still being investigated and its anti-diabetic and anti-hypertensive effects have been found. The action mechanisms for anti-diabetes are being determined. (Click Figures to Enlarge)
We already reported that Globin Peptide prevented the intra-abdominal fat (visceral fat) accumulation in dietary obese mice.
Based on the above effects, Globin Peptide has become a health food ingredient utilized for preventing and treating metabolic syndrome.
All That Began with Pig's Weight Loss!
The pig had lost his weight after ingesting the protein digests which were under development. Actually, that experiment was failure but it led to the birth of our current product “Globin Peptide” by reverse thinking.
We have got several world patents about decreasing the triglyceride levels by food protein digests including Globin Peptide.
In 1998 we finally had gotten the FOSHU status for our product “Napple Drink” containing Globin Peptide as an active ingredient.
■ Action of Globin Peptide
【To Top】
■ Clinical Effects
Clinical studies of Globin Peptide were carried out not only by us but also by third-party organizations including foreign companies and Japanese goverment.
● Inhibition of Postprandial Hypertriglyceridemia
We shows the data abstracted from one of our articles “Hypotriglyceridemic effects of globin digest on subjects with borderline hyperlipidemia” (Kagawa K et al: J Jpn Soc Nutr Food Sci, 52, 71-77 (1999) in Japanese).
[METHODS] This clinical test was carried out using single-blind crossover trial with six of borderline hyperlipidemic Japanese. Washout period was 7 days. These subjects ingested thick soup containing 40g of butter with or without 1g of globin peptide.
[RESULTS] As shown the above figure, Globin Peptide significantly inhibited the increased serum triglyceride levels from 1hr to 6hr after ingestion of fat meal, and also decreased AUC (0-6hr) by 42% of control group (p<0.01) .
● Decrease of Postprandial Remnant-like Lipoprotein
There is considerable evidence to indicate that elevated levels of plasma triglyceride-rich lipoprotein remnants are associated with increased risk of premature cardiovascular disease, and then with a direct effect of remnant lipoproteins on arterial lipid accumulation and lesion formation. Increased plasma remnant-like lipoprotein-cholesterol (RLP-C) levels are clearly associated with increased risk of disease and can be significantly reduced by lipid-lowering therapy (Twickler TB et al:Circulation,109,1918 (2004) ). Terefore we determined RLP-C levels after fat-load with or without globin peptide(See above Methods).
[RESULTS] Globin Peptide inhibited postprandial increased RLP-C level at early period, and decreased its AUC(0-6hr) to 50% of control.
● Decrease of Fasting Blood Triglyceride
[PROTOCOL]
Subjects : 89 Chinese volunteers (Control: 44, Experiment: 45)
Design : Randomized placebo controlled study
Dosage : 1500 mg/day (each 500 mg, three times a day) for 70 days
[RESULTS] Significant Reduction in Serum Triglyceride (p<0.05)
● Decrease of Body Fat
[PROTOCOL] Same as above
[RESULTS] Body fat after 42 days ingestion of globin peptide significantly decreased 2.0% compared with pre-ingestion (p<0.05), and finally its reduction was 2.4% on 70th day. After 28 days follow-up periods further 0.9% reduction in body fat was observed, but its difference between control and Globin Peptide groups was not statistically significant.
● Decrease of Fasting Blood Triglyceride in Type 2 Diabetes Mellitus
[PROTOCOL]
Period: each 4 Weeks of guava tea, Globin Peptide, and combination
Subjects: 30 Japanese Diabetic Patients
Design: Well Controlled Study
Dosage of Globin Peptide: 2000 mg/day (1000 mg twice a day)
[RESULTS] Significant Reduction in Fasting Serum Triglyceride (p<0.05) and Increase of HDL-Cholesterol
● Decrease of Fasting Blood Triglyceride in Hyperlipidemic Subjects
[PROTOCOL]
Subjects : 4 Japanese volunteers
Design : Well controlled study
Dosage : 2000 mg/day (each 1000 mg, twice a day) for 6 month
[RESULTS] Significant Reduction in Serum Triglyceride
● Improvement of Blood Glucose in Type 2 Diabetic Subjects
[PROTOCOL]
Subjects : 100 Chinese type 2 diabetic patients (Control: 50, Experiment: 50)
Design : Randomized placebo controlled study
Dosage : 2 g/day (each 1 g, two times a day) for 30 days
[RESULTS] Stastically Significant reduction of fasting blood glucose level (p<0.05)
[RESULTS] Significant Inhibition of postprandial blood glucose elevation (2 hr after meal) (p<0.05)
● Improvement of Blood Pressure in Mild Hypertensive Patients
[PROTOCOL]
Subjects : 89 Chinese volunteers (Control: 44, Experiment: 45)
Design : Randomized placebo controlled study
Dosage : 1500 mg/day (each 500 mg, three times a day) for 70 days
[RESULTS] Significant Reduction of Diastolic pressure in Mild Hypertensive Patients (p<0.05)
● Action Mechanisms
Mechanisms of triglyceride (TG) lowering effect of Globin Peptide are as follows; Globin Peptide
1) decrease lipid absorption by inhibition of pancreatic lipase,
2) enhances elimination of TG from blood by activation of lipoprotein lipase and hepatic triglyceride lipase, and enhances degradation of fatty acid by activation of β-oxidation in mitochondria and by proliferation of peroxisome containing catalase, and
3) inhibits hypertrophy of adipocytes and differentiation of fibroblasts to adipocytes.
We are showing various evidence as more fully described below.
■ Effects
Recently we are studying with a focus on antidiabetic and antihypertensive effects of Globin Peptide.
● In vitro Pancreatic Lipase
When it was showed that Globin Peptide has inhibited fecal excretion of fat in pig using single blind test, we studied the effect of Globin Peptide on pancreatic lipase in vitro.
[INCUBATION SYSTEM] 34 u/mL of pancreatic lipase (type-VI-S, pig origin, 10000 µ/mg), 40 µmole/mL of triolein, 0.22 mg/ml of taurocholate sodium, 2 mg/mL of arabic gum, and 4, 20. 40 mg/mL of Globin Peptide in TES-NaCl buffer (pH 7.0).
[RESULTS] 40 mg/mL of Globin Peptide significantly inhibited pig pancreatic lipase activity to 60% of control (no addtion of Globin Peptide).
Globin Peptide Concentration used in this experiment are correspondent to its concentration calculated from 1g dose of Globin Peptide and volume of human gastric jucie.
This result suggest that Globin Peptide reduces fat absorption by inhibition of pancreatic lipase.
● Lipoprotein Lipase and Hepatic Triglyceride Lipase
Lipoprotein lipase (LPL) plays a central role in lipoprotein metabolism by catalyzing the hydrolysis of both dietary and endogenous triglycerides in chylomicrons and very low density lipoprotein particles. Hepatic triglyceride lipase (HTGL) localizes on hepatic endotherial cell surface and catbolize mainly chylomicrons from portal vein. Increase of these enzyme activities decrease blood triglyceride levels. We studyed whether Globin Peptide enhances these lipases in post-heparin plasma.
[DESIGN] Ten subjects (normolipidemic 7, borderline lipidemic 2, hyperlipidemic 1), 2-period crossover study including high fat (40 g) diets with of without Globin Peptide and 2-wk washout periods. Blood was collected 170min after meal.
[RESULT] The triglyceride level after fat meal was 174±31 mg/dL in control (without Globin Peptide) group and 127±22 mg/dL (73% of control) in Globin Peptide group. It was confirmed that Globin Peptide inhibits postprandial hyperlipidemia. In control group LPL activities (control) was 241±22 µg/ml, and HTGL was 16.4±1.7 µmol/ml/hr. As shown in figure, Globin Peptide increases LPL (155% of control, p<0.01) and HTGL (122%, p<0.05). In addition significant positive coreration between blood triglyceride levels and LPL activities was found, and in Globin Peptide group the correlation line was sifted to left. Globin Peptide appear to lower the increased triglyceride level by increae of LPL and HTGL.
● Insulin Secretion
Globin Peptide enhanced lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities catabolizing triglyceride as menthioned above. It is not well unknown the mechanism that cause expression of these enzymes or/and its exocytotic secretion to plasma memmbranes, but insulin may be one of its candidates. So we determined blood insulin level in six normal subjects after oral ingestion of Globin Peptide using cross-over trial.
[RESULTS] Insulin AUC of control was 8.7±1.14 µuniti/mL/3hrs. Globin Peptide of 3g significantly increased AUC to 183% of control (p<0.05). Increased insulin level by Globin Peptide may cause inhibition of postprandial triglyceride elevation.
● Mouse Hepatic PPAR-α Activity
We examined the effect of globin peptide on fatty acid metabolism, particularly mitochondorial and peroxisomal fatty acid oxidations in liver.
After 10-20 days feeding of high fat diet in which protein was replaced by globin peptide in 16-50%, hepatic catalase activity as a marker of peroxisome, increased nearly to the same extent as the case of addition of 0.125% hypolipidemic drug clofibrate in mice.
Very long chain fatty acids (C20 or more) are oxidized in peroxisome. The enzymes in peroxisomes do not attack shorter chain fatty acids. Octanoyl and acetyl groups are subsequently removed from the peroxisomes in the forms of octanoyl and acetyl carnitine, and both are further oxidized in mitochondria.(from Harper's Biochemistry)
Our result shows that globin peptide enhances very long fatty acid catabolism probably via increased PPAR-α activities. Recently it was confirmed that Globin Peptide increased PPAR-α expression itself in hepatocyte in vitro.
● Fatty Acid β-Oxidation
Fatty acids are converted to acetyl CoA by β-oxidation in mitochondria and/or in peroxisomes, and acetyl CoA are used in Krebs cycle and finally some of carbon atoms separated from fatty acids are excreted into exhalation. Therefore, radioacitivities in expired gas after administration of C14-labeled triolein exhibits extent of β-oxidation of fatty acids.
Globin Peptide significantly increased the radioactivities in exhalation compared to that of control especially at early time of oil ingestion.
These results suggest that Globin Peptide enhances β-oxidation in mitochondria and peroxisomes.
● Adipogenic Differentiation of Fibroblast
● Visceral Fat Accumuration in High Calorie Diets
● Rebound of Blood Cholesterol, TG or Glucose
● Blood Glucose Elevation in Mice GTT
● Blood Glucose Level in Diabetic Mice
● Blood Pressure in SHR
■ Safety
● Clinical
- No hepatic and renal toxicities were observed in high dose ingestion (3g Globin Peptide/day) for 2 months.
- Antigenicity: No case report was found.
- Addiction: No addiction of Globin Peptide effects were observed.
● Toxicological
- Acute Toxicity: male mice, Lethal Dose (p.o.)
Results: over 10g/kg body weight
- Subacute Toxicity: male rats, Globin Peptide 4g/kg/day (p.o.) for 3 months
Results: No toxic reactions were observed.
- Mutagenic Studies:
- Chromosomal Aberration Test on Mammalian Cells
- Reverse Mutation Test on Bacteria
- Micronucleous Test on Mice
Results: No clastogenic activity in vivo and in vitro was found.
■ Product
- Trade Name: BOREP GD
- Appearance: cream to light brown powder
- Protein: > 85%
- Average peptide length: 3 - 5
- Ash: < 6%
- Moisture: < 5%
- Active Peptide (Var-Var-Tyr-Pro): > 0.6%
- Processing: heat- and acid-stable
- Solubility: highly soluble and clear in water
■ References
- Matsutaka H, Fukuhama C, Isono M, Fujii K, Kagawa K
Jpn J Pharmacol, 58 (Supple I), 80P (1992).
"Effect of oligopeptides on lipid metabolism. 3) Effect of oligopeptides from various protein digestants on lipid abnormalities in serum and liver."
[Abstract] We found out the serum triglyceride-lowering effect of oligopeptides from various protein digestants, in which globin digest showed the maximum activity. Their mode of action is dose-dependent and does not show species specificity. Additional effects of oligopeptides on lipid metabolism such as hepatic triglyceride lipase activity, fatty acid synthesis and fat deposition in adipose tissue have been studied. In this report, we examined the effect of oligopeptides on fatty acid metabolism, particularly mitochondorial and peroxisomal fatty acid oxidation in liver. After 10-20 days feeding of high fat diet in which protein was replaced by globin digest in 16-50%, hepatic catalase activity was increased nearly to the same extent as the case of addition of 0.125% clofibrate in mice.
- Watanabe S, Matsutaka H, Numata M, Nakamura T, Fukuhama C, Noma S, Kagawa K
Jpn J Pharmacol, 61(Suppl Ⅰ), 79P (1993).
"Effect of oligopeptides on lipid metabolism. 4) in vivo and in vitro effects on adipocyte differentiation."
[Abstract] We already showed that oligopeptides from various protein digestants affect triglyceride level in blood, triglyceride lipase activity, fatty acid synthesis and fatty acid oxidation in liver, and fat deposition in adipose tissues. 0ne of protein digestants, globin digest (GD), has the maximum activity. DNA content in adipose tissue of obese mice increased 1.5 times the level of control diet group after 3 weeks feeding of high fat diet, whereas the increase of DNA was depressed by subsitution of 25% protein for GD in the diet. Its inhibitory effect on adipocyte conversion was also observed in vitro examination with Swiss mouse 3T3‐L1 cells. When cells were treated with 10, 20, 40, and 80μg/ml of GD for 48hr before and after induction by insulin, 1-methyl-3-isobutylxanthine and dexamethasone for 48hr, GDPH activities were dramatically decreased depending on its concentration in culture medium. We also examined some of oligopeptide fractions obtained by reversed-phase chromatography. In addition, in vivo treatment of GD increased in vitro lipolytic activity of adipose tissue. These results suggest that some oligopeptide fraction of globin digest inhibits adipocyte differentiation and some oligopeptide enhances lipolytic activity in adipocyte.
- Kagawa K, Matsutaka H, Fukuhama C, Watanabe Y, Fujino H
Life Sci, 58(20), 1745-1755 (1996).
"Globin digest, acidic protease hydrolysate, inhibits dietary hypertriglyceridemia and Val-Val-Tyr-Pro, one of its constituents, possesses most superior effect"
[Summary] Globindigest(GD), prepared from globin by acidic protease treatment，suppressed the elevation of serum triglyceride level in not only total but also chylomicron fraction affter oral administration of olive oil. By screening with this lowerlng activity, we concluded that Val-Val-Tyr-Pro (VVYP) would be most effective constituent having hypotriglyceridemic action in GD. The mode of their action was dose dependent and did not show species specincity. Neither the repression of peristaltic movement of intestine nor the delaying of gastric emptylng wascaused by intake of GD or VVYP, however, the excretion of administered lipid was much more than that of control. Furthermore, administration of GD caused more prominent activation of hepatic triglyceridelipase (HTGL) and the increase of hepatic free fatty acid (FFA) concentration in early phase after administration of fat. From these results, it could be elucidated that GD, and also VVYP, inhibited fat absorption from digestive tract and enhanced activity of HTGL，so that more rapid clearance of dietary hypertriglyceridemia was caused.
- Kagawa K, Matsutaka H, Fukuhama C, Fujino H, Okuda H
J Nutr, 128(1), 56-60 (1998).
"Suppressive Effect of Globin Digest on Postprandial Hyperlipidemia in Male Volunteers"
[ABSTRACT] We have reported previously that various edible protein digests inhibit dietary hyperlipidemia in mice, rats, pigs and dogs. Of the various digests tested, globin digest had the most potent inhibitory activity, and a tetrapeptide extracted from globin digest, Val-Val-Tyr-Pro, had activity 7000-fold greater than that of the parent digest. In this clinical study, we investigated the influence of globin digest on serum chylomicron triglyceride concentrations as an indicator of the effect of globin digest on fat absorption and catabolism in humans. Parallel and crossover trials were conducted in which men consumed a control high fat diet (25g fat, 7.6g carbohydrate, 1.9g protein and 0.7g sodium chloride) or the same diet supplemented with globin digest. The supplemented dosages were 1 and 4g globin digest. In the parallel trial, 22 men were divided into three groups: control, globin digest 1g and globin digest 4g. The increases in chylomicron triglyceride concentrations at 1 h after ingestion of 1 or 4 g globin digest were significantly lower (P<0.05) compared with the control group. The crossover trial involved six subjects who consumed the control high fat diet and the same diet supplemented with 4g globin digest. Serum chylomicron triglyceride levels increased in both groups at 1 and 2 h after ingestion, but when subjects consumed 4g globin digest the increases were suppressed to 75 (P<0.05) and 42% (P<0.05) of the increases in controls at the corresponding times, respectively. The areas under the curves of chylomicron and serum total triglyceride concentrations during the 4h after ingestion of 4g globin digest were 46 (P<0.05) and 34% (P<0.05) lower, respectively, than when the men consumed the high fat control diet. In these trials, globin digest reduced the increase in serum chylomicron triglyceride concentrations as a result of the ingestion of a high fat diet. This hypotriglyceridemic effect of globin digest may be valuable for preventing obesity and in lowering the incidence of cardiovascular diseases.
- Kagawa K, Fukuhama C, Fujino H, Okuda H
J Jpn Soc Nutr Food Sci, 52, 71-77 (1999)(in Japanese).
"Hypotriglyceridemic Effect of Globin Digest on Subjects with Borderline Hyperlipidemia"
[Summary] It has already been reported that globin digest（GD）exerts a hypotriglyceridemic action in laboratory animals and humans. A tetrapeptide, Val-Val-Tyr-Pro, extracted from GD, has also been shown to be 7000-times more active than the parent GD. We studied the hypotriglyceridemic effect of GD in subjects with borderline hyperlipidemia. In normal subjects, 1g of GD showed sufficient hypotriglyceridemic action. When borderline hypertriglyceridemic subjects were administered 1g of GD as a beverage with 40g of fat, the increases in serum and chylomicron(CM) TGs at 1-5h after the administration were suppressed to 25-50% of the control values(without GD). The areas under the serum TG and CM-TG concentration curves(AUCs；0-6h) were significantly decreased to about 40% of the control, respectively. GD enhanced the elimination rate constants of TG and CM-TG in borderline hypertriglyceridemic subjects, and showed a more effective hypotriglyceridemic action than in normal subjects. GD thus appears to be useful for prevention of cardiovascular disease and atherosclerosis in subjects with borderline hypertriglyceridemia.
■ Patents
- EU 0420979B1 : Lipid metabolism improving agent and method of use
- US 5,723,443 : Lipid metabolism promoting agent and its use
- US 5,958,885 : Peptide and formulations thereof inhibiting elevations of triglyceride levels in blood
- US 6,046,168 : Peptide inhibits blood triglyceride level
- AU-B-30370/89: Lipid metabolism improving agent and its method of use
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【To Top】
■ Clinical Effects
Clinical studies of Globin Peptide were carried out not only by us but also by third-party organizations including foreign companies and Japanese goverment.
● Inhibition of Postprandial Hypertriglyceridemia
We shows the data abstracted from one of our articles “Hypotriglyceridemic effects of globin digest on subjects with borderline hyperlipidemia” (Kagawa K et al: J Jpn Soc Nutr Food Sci, 52, 71-77 (1999) in Japanese).
[METHODS] This clinical test was carried out using single-blind crossover trial with six of borderline hyperlipidemic Japanese. Washout period was 7 days. These subjects ingested thick soup containing 40g of butter with or without 1g of globin peptide.
[RESULTS] As shown the above figure, Globin Peptide significantly inhibited the increased serum triglyceride levels from 1hr to 6hr after ingestion of fat meal, and also decreased AUC (0-6hr) by 42% of control group (p<0.01) .
● Decrease of Postprandial Remnant-like Lipoprotein
There is considerable evidence to indicate that elevated levels of plasma triglyceride-rich lipoprotein remnants are associated with increased risk of premature cardiovascular disease, and then with a direct effect of remnant lipoproteins on arterial lipid accumulation and lesion formation. Increased plasma remnant-like lipoprotein-cholesterol (RLP-C) levels are clearly associated with increased risk of disease and can be significantly reduced by lipid-lowering therapy (Twickler TB et al:Circulation,109,1918 (2004) ). Terefore we determined RLP-C levels after fat-load with or without globin peptide(See above Methods).
[RESULTS] Globin Peptide inhibited postprandial increased RLP-C level at early period, and decreased its AUC(0-6hr) to 50% of control.
● Decrease of Fasting Blood Triglyceride
[PROTOCOL]
Subjects : 89 Chinese volunteers (Control: 44, Experiment: 45)
Design : Randomized placebo controlled study
Dosage : 1500 mg/day (each 500 mg, three times a day) for 70 days
[RESULTS] Significant Reduction in Serum Triglyceride (p<0.05)
● Decrease of Body Fat
[PROTOCOL] Same as above
[RESULTS] Body fat after 42 days ingestion of globin peptide significantly decreased 2.0% compared with pre-ingestion (p<0.05), and finally its reduction was 2.4% on 70th day. After 28 days follow-up periods further 0.9% reduction in body fat was observed, but its difference between control and Globin Peptide groups was not statistically significant.
● Decrease of Fasting Blood Triglyceride in Type 2 Diabetes Mellitus
[PROTOCOL]
Period: each 4 Weeks of guava tea, Globin Peptide, and combination
Subjects: 30 Japanese Diabetic Patients
Design: Well Controlled Study
Dosage of Globin Peptide: 2000 mg/day (1000 mg twice a day)
[RESULTS] Significant Reduction in Fasting Serum Triglyceride (p<0.05) and Increase of HDL-Cholesterol
● Decrease of Fasting Blood Triglyceride in Hyperlipidemic Subjects
[PROTOCOL]
Subjects : 4 Japanese volunteers
Design : Well controlled study
Dosage : 2000 mg/day (each 1000 mg, twice a day) for 6 month
[RESULTS] Significant Reduction in Serum Triglyceride
● Improvement of Blood Glucose in Type 2 Diabetic Subjects
[PROTOCOL]
Subjects : 100 Chinese type 2 diabetic patients (Control: 50, Experiment: 50)
Design : Randomized placebo controlled study
Dosage : 2 g/day (each 1 g, two times a day) for 30 days
[RESULTS] Stastically Significant reduction of fasting blood glucose level (p<0.05)
[RESULTS] Significant Inhibition of postprandial blood glucose elevation (2 hr after meal) (p<0.05)
● Improvement of Blood Pressure in Mild Hypertensive Patients
[PROTOCOL]
Subjects : 89 Chinese volunteers (Control: 44, Experiment: 45)
Design : Randomized placebo controlled study
Dosage : 1500 mg/day (each 500 mg, three times a day) for 70 days
[RESULTS] Significant Reduction of Diastolic pressure in Mild Hypertensive Patients (p<0.05)
● Action Mechanisms
Mechanisms of triglyceride (TG) lowering effect of Globin Peptide are as follows; Globin Peptide
1) decrease lipid absorption by inhibition of pancreatic lipase,
2) enhances elimination of TG from blood by activation of lipoprotein lipase and hepatic triglyceride lipase, and enhances degradation of fatty acid by activation of β-oxidation in mitochondria and by proliferation of peroxisome containing catalase, and
3) inhibits hypertrophy of adipocytes and differentiation of fibroblasts to adipocytes.
We are showing various evidence as more fully described below.
■ Effects
Recently we are studying with a focus on antidiabetic and antihypertensive effects of Globin Peptide.
● In vitro Pancreatic Lipase
When it was showed that Globin Peptide has inhibited fecal excretion of fat in pig using single blind test, we studied the effect of Globin Peptide on pancreatic lipase in vitro.
[INCUBATION SYSTEM] 34 u/mL of pancreatic lipase (type-VI-S, pig origin, 10000 µ/mg), 40 µmole/mL of triolein, 0.22 mg/ml of taurocholate sodium, 2 mg/mL of arabic gum, and 4, 20. 40 mg/mL of Globin Peptide in TES-NaCl buffer (pH 7.0).
[RESULTS] 40 mg/mL of Globin Peptide significantly inhibited pig pancreatic lipase activity to 60% of control (no addtion of Globin Peptide).
Globin Peptide Concentration used in this experiment are correspondent to its concentration calculated from 1g dose of Globin Peptide and volume of human gastric jucie.
This result suggest that Globin Peptide reduces fat absorption by inhibition of pancreatic lipase.
● Lipoprotein Lipase and Hepatic Triglyceride Lipase
Lipoprotein lipase (LPL) plays a central role in lipoprotein metabolism by catalyzing the hydrolysis of both dietary and endogenous triglycerides in chylomicrons and very low density lipoprotein particles. Hepatic triglyceride lipase (HTGL) localizes on hepatic endotherial cell surface and catbolize mainly chylomicrons from portal vein. Increase of these enzyme activities decrease blood triglyceride levels. We studyed whether Globin Peptide enhances these lipases in post-heparin plasma.
[DESIGN] Ten subjects (normolipidemic 7, borderline lipidemic 2, hyperlipidemic 1), 2-period crossover study including high fat (40 g) diets with of without Globin Peptide and 2-wk washout periods. Blood was collected 170min after meal.
[RESULT] The triglyceride level after fat meal was 174±31 mg/dL in control (without Globin Peptide) group and 127±22 mg/dL (73% of control) in Globin Peptide group. It was confirmed that Globin Peptide inhibits postprandial hyperlipidemia. In control group LPL activities (control) was 241±22 µg/ml, and HTGL was 16.4±1.7 µmol/ml/hr. As shown in figure, Globin Peptide increases LPL (155% of control, p<0.01) and HTGL (122%, p<0.05). In addition significant positive coreration between blood triglyceride levels and LPL activities was found, and in Globin Peptide group the correlation line was sifted to left. Globin Peptide appear to lower the increased triglyceride level by increae of LPL and HTGL.
● Insulin Secretion
Globin Peptide enhanced lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities catabolizing triglyceride as menthioned above. It is not well unknown the mechanism that cause expression of these enzymes or/and its exocytotic secretion to plasma memmbranes, but insulin may be one of its candidates. So we determined blood insulin level in six normal subjects after oral ingestion of Globin Peptide using cross-over trial.
[RESULTS] Insulin AUC of control was 8.7±1.14 µuniti/mL/3hrs. Globin Peptide of 3g significantly increased AUC to 183% of control (p<0.05). Increased insulin level by Globin Peptide may cause inhibition of postprandial triglyceride elevation.
● Mouse Hepatic PPAR-α Activity
We examined the effect of globin peptide on fatty acid metabolism, particularly mitochondorial and peroxisomal fatty acid oxidations in liver.
After 10-20 days feeding of high fat diet in which protein was replaced by globin peptide in 16-50%, hepatic catalase activity as a marker of peroxisome, increased nearly to the same extent as the case of addition of 0.125% hypolipidemic drug clofibrate in mice.
Very long chain fatty acids (C20 or more) are oxidized in peroxisome. The enzymes in peroxisomes do not attack shorter chain fatty acids. Octanoyl and acetyl groups are subsequently removed from the peroxisomes in the forms of octanoyl and acetyl carnitine, and both are further oxidized in mitochondria.(from Harper's Biochemistry)
Our result shows that globin peptide enhances very long fatty acid catabolism probably via increased PPAR-α activities. Recently it was confirmed that Globin Peptide increased PPAR-α expression itself in hepatocyte in vitro.
● Fatty Acid β-Oxidation
Fatty acids are converted to acetyl CoA by β-oxidation in mitochondria and/or in peroxisomes, and acetyl CoA are used in Krebs cycle and finally some of carbon atoms separated from fatty acids are excreted into exhalation. Therefore, radioacitivities in expired gas after administration of C14-labeled triolein exhibits extent of β-oxidation of fatty acids.
Globin Peptide significantly increased the radioactivities in exhalation compared to that of control especially at early time of oil ingestion.
These results suggest that Globin Peptide enhances β-oxidation in mitochondria and peroxisomes.
● Adipogenic Differentiation of Fibroblast
● Visceral Fat Accumuration in High Calorie Diets
● Rebound of Blood Cholesterol, TG or Glucose
● Blood Glucose Elevation in Mice GTT
● Blood Glucose Level in Diabetic Mice
● Blood Pressure in SHR
■ Safety
● Clinical
- No hepatic and renal toxicities were observed in high dose ingestion (3g Globin Peptide/day) for 2 months.
- Antigenicity: No case report was found.
- Addiction: No addiction of Globin Peptide effects were observed.
● Toxicological
- Acute Toxicity: male mice, Lethal Dose (p.o.)
- Results: over 10g/kg body weight
- Subacute Toxicity: male rats, Globin Peptide 4g/kg/day (p.o.) for 3 months
- Results: No toxic reactions were observed.
- Mutagenic Studies:
- Chromosomal Aberration Test on Mammalian Cells
- Reverse Mutation Test on Bacteria
- Micronucleous Test on Mice
- Results: No clastogenic activity in vivo and in vitro was found.
■ Product
- Trade Name: BOREP GD
- Appearance: cream to light brown powder
- Protein: > 85%
- Average peptide length: 3 - 5
- Ash: < 6%
- Moisture: < 5%
- Active Peptide (Var-Var-Tyr-Pro): > 0.6%
- Processing: heat- and acid-stable
- Solubility: highly soluble and clear in water
■ References
- Matsutaka H, Fukuhama C, Isono M, Fujii K, Kagawa K
- Watanabe S, Matsutaka H, Numata M, Nakamura T, Fukuhama C, Noma S, Kagawa K
- Kagawa K, Matsutaka H, Fukuhama C, Watanabe Y, Fujino H
- Kagawa K, Matsutaka H, Fukuhama C, Fujino H, Okuda H
- Kagawa K, Fukuhama C, Fujino H, Okuda H
- Jpn J Pharmacol, 58 (Supple I), 80P (1992).
"Effect of oligopeptides on lipid metabolism. 3) Effect of oligopeptides from various protein digestants on lipid abnormalities in serum and liver."
[Abstract] We found out the serum triglyceride-lowering effect of oligopeptides from various protein digestants, in which globin digest showed the maximum activity. Their mode of action is dose-dependent and does not show species specificity. Additional effects of oligopeptides on lipid metabolism such as hepatic triglyceride lipase activity, fatty acid synthesis and fat deposition in adipose tissue have been studied. In this report, we examined the effect of oligopeptides on fatty acid metabolism, particularly mitochondorial and peroxisomal fatty acid oxidation in liver. After 10-20 days feeding of high fat diet in which protein was replaced by globin digest in 16-50%, hepatic catalase activity was increased nearly to the same extent as the case of addition of 0.125% clofibrate in mice.
- Jpn J Pharmacol, 61(Suppl Ⅰ), 79P (1993).
"Effect of oligopeptides on lipid metabolism. 4) in vivo and in vitro effects on adipocyte differentiation."
[Abstract] We already showed that oligopeptides from various protein digestants affect triglyceride level in blood, triglyceride lipase activity, fatty acid synthesis and fatty acid oxidation in liver, and fat deposition in adipose tissues. 0ne of protein digestants, globin digest (GD), has the maximum activity. DNA content in adipose tissue of obese mice increased 1.5 times the level of control diet group after 3 weeks feeding of high fat diet, whereas the increase of DNA was depressed by subsitution of 25% protein for GD in the diet. Its inhibitory effect on adipocyte conversion was also observed in vitro examination with Swiss mouse 3T3‐L1 cells. When cells were treated with 10, 20, 40, and 80μg/ml of GD for 48hr before and after induction by insulin, 1-methyl-3-isobutylxanthine and dexamethasone for 48hr, GDPH activities were dramatically decreased depending on its concentration in culture medium. We also examined some of oligopeptide fractions obtained by reversed-phase chromatography. In addition, in vivo treatment of GD increased in vitro lipolytic activity of adipose tissue. These results suggest that some oligopeptide fraction of globin digest inhibits adipocyte differentiation and some oligopeptide enhances lipolytic activity in adipocyte.
- Life Sci, 58(20), 1745-1755 (1996).
"Globin digest, acidic protease hydrolysate, inhibits dietary hypertriglyceridemia and Val-Val-Tyr-Pro, one of its constituents, possesses most superior effect"
[Summary] Globindigest(GD), prepared from globin by acidic protease treatment，suppressed the elevation of serum triglyceride level in not only total but also chylomicron fraction affter oral administration of olive oil. By screening with this lowerlng activity, we concluded that Val-Val-Tyr-Pro (VVYP) would be most effective constituent having hypotriglyceridemic action in GD. The mode of their action was dose dependent and did not show species specincity. Neither the repression of peristaltic movement of intestine nor the delaying of gastric emptylng wascaused by intake of GD or VVYP, however, the excretion of administered lipid was much more than that of control. Furthermore, administration of GD caused more prominent activation of hepatic triglyceridelipase (HTGL) and the increase of hepatic free fatty acid (FFA) concentration in early phase after administration of fat. From these results, it could be elucidated that GD, and also VVYP, inhibited fat absorption from digestive tract and enhanced activity of HTGL，so that more rapid clearance of dietary hypertriglyceridemia was caused.
- J Nutr, 128(1), 56-60 (1998).
"Suppressive Effect of Globin Digest on Postprandial Hyperlipidemia in Male Volunteers"
[ABSTRACT] We have reported previously that various edible protein digests inhibit dietary hyperlipidemia in mice, rats, pigs and dogs. Of the various digests tested, globin digest had the most potent inhibitory activity, and a tetrapeptide extracted from globin digest, Val-Val-Tyr-Pro, had activity 7000-fold greater than that of the parent digest. In this clinical study, we investigated the influence of globin digest on serum chylomicron triglyceride concentrations as an indicator of the effect of globin digest on fat absorption and catabolism in humans. Parallel and crossover trials were conducted in which men consumed a control high fat diet (25g fat, 7.6g carbohydrate, 1.9g protein and 0.7g sodium chloride) or the same diet supplemented with globin digest. The supplemented dosages were 1 and 4g globin digest. In the parallel trial, 22 men were divided into three groups: control, globin digest 1g and globin digest 4g. The increases in chylomicron triglyceride concentrations at 1 h after ingestion of 1 or 4 g globin digest were significantly lower (P<0.05) compared with the control group. The crossover trial involved six subjects who consumed the control high fat diet and the same diet supplemented with 4g globin digest. Serum chylomicron triglyceride levels increased in both groups at 1 and 2 h after ingestion, but when subjects consumed 4g globin digest the increases were suppressed to 75 (P<0.05) and 42% (P<0.05) of the increases in controls at the corresponding times, respectively. The areas under the curves of chylomicron and serum total triglyceride concentrations during the 4h after ingestion of 4g globin digest were 46 (P<0.05) and 34% (P<0.05) lower, respectively, than when the men consumed the high fat control diet. In these trials, globin digest reduced the increase in serum chylomicron triglyceride concentrations as a result of the ingestion of a high fat diet. This hypotriglyceridemic effect of globin digest may be valuable for preventing obesity and in lowering the incidence of cardiovascular diseases.
- J Jpn Soc Nutr Food Sci, 52, 71-77 (1999)(in Japanese).
"Hypotriglyceridemic Effect of Globin Digest on Subjects with Borderline Hyperlipidemia"
[Summary] It has already been reported that globin digest（GD）exerts a hypotriglyceridemic action in laboratory animals and humans. A tetrapeptide, Val-Val-Tyr-Pro, extracted from GD, has also been shown to be 7000-times more active than the parent GD. We studied the hypotriglyceridemic effect of GD in subjects with borderline hyperlipidemia. In normal subjects, 1g of GD showed sufficient hypotriglyceridemic action. When borderline hypertriglyceridemic subjects were administered 1g of GD as a beverage with 40g of fat, the increases in serum and chylomicron(CM) TGs at 1-5h after the administration were suppressed to 25-50% of the control values(without GD). The areas under the serum TG and CM-TG concentration curves(AUCs；0-6h) were significantly decreased to about 40% of the control, respectively. GD enhanced the elimination rate constants of TG and CM-TG in borderline hypertriglyceridemic subjects, and showed a more effective hypotriglyceridemic action than in normal subjects. GD thus appears to be useful for prevention of cardiovascular disease and atherosclerosis in subjects with borderline hypertriglyceridemia.
■ Patents
- EU 0420979B1 : Lipid metabolism improving agent and method of use
- US 5,723,443 : Lipid metabolism promoting agent and its use
- US 5,958,885 : Peptide and formulations thereof inhibiting elevations of triglyceride levels in blood
- US 6,046,168 : Peptide inhibits blood triglyceride level
- AU-B-30370/89: Lipid metabolism improving agent and its method of use
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